4(2-Phenyl-o-totyl)-3,5-disubstituted-4h-1,2,4,-triazoles

ABSTRACT

Compounds of the formula II   wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, cycloalkyl of 3 to 8 carbon atoms, inclusive, phenyl, benzyl, pyridyl; wherein R&#39;&#39; and R&#39;&#39;&#39;&#39; are alkyl defined as above, or together   IS PYRROLIDINO, PIPERIDINO, AND MORPHOLINO; WHEREIN R2, R3, R4, and R5 are hydrogen, alkyl as defined above, halogen, or trifluoromethyl, are produced by applying a Mannich reaction to a compound of the formula I:   wherein R1, R2, R3, R4, and R5 are defined as above. The compounds of formula II have activity per se or as pharmacologically acceptable acid addition salts as sedatives, hypnotics, anticonvulsants, tranquilizers, and muscle relaxants in mammals and birds, also as feed additives for increasing growth rate and feed efficiency of livestock and poultry. They can also be used as intermediates for other active compounds, such as the corresponding benzophenone type compounds (IV) produced from II by oxidation.

Gall

United States Patent [19] [451 Oct. 21, 19754(2-PHENYL-O-TOLYL)-3,5-DISUBSTITUT- ED-4H- l,2,4,-TRIAZOLES Inventor:Martin Gall, Kalamazoo, Mich.

The Upjohn Company, Kalamazoo, Mich.

Filed: Aug. 13, 1973 Appl. No.: 387,761

Published under the Trial Voluntary Protest Program on January 28, l975as document no. B 387,761.

Related US. Application Data Continuation-impart of Ser. No. 172.920,Aug. 18, 1971, abandoned.

Assignee:

US. Cl.... 260/308 R; 260/247.l; 260/2472 R; 260/2475 E; 260/293.69;260/294.8 R; 260/294.8 E; 260/295 D; 260/295 S; 260/296 R; 260/558 H;424/248; 424/263;

Int. Cl. ..C07D 249/08; C07D 265/301 c071) 21l/l4; C07D 207/06 Field ofSearch 260/308 R, 296 R, 293.69, 260/2476 E References Cited OTHERPUBLICATIONS Gall, Chemical Abstracts, Vol. 78, Abstract No. 136. 302t1973).

Primary Examiner-Alton D. Rollins Attorney, Agent, or Firm-Hans L.Berneis ABSTRACT Compounds of the formula ll wherein R is selected fromthe group consisting of hydrogen, alkyl of l to 3 carbon atoms,inclusive, cycloalkyl of 3 to 8 carbon atoms, inclusive, phenyl, benzyl,pyridyl; wherein R and R" are alkyl defined as above, or together ispyrrolidino, piperidino. and morpholino; wherein R R R and R arehydrogen. alkyl as defined above, halogen, or trifluoromethyl, areproduced by applying a Mannich reaction to a compound of the formula I:

wherein R R R R and R are defined as above. The compounds of formulja llhave activity per se or as pharmacologically acceptable acid additionsalts as sedatives, hypnotics, anticonvulsants, tranquilizers. andmuscle relaxants in mammals and birds, also as feed additives forincreasing growth rate and feed efficiency of livestock and poultry.They can also be used as intermediates for other active compounds, suchas the corresponding benzophenone type compounds (lV) produced from llbyoxidation.

5 ClaimsQNo Drawings 4(a-PHENYL-o-TOLYL)-3,5-DISUBSTITUTED-4H-l,2,4,-TRIAZOLES CROSS REFERENCE TO RELATED APPLICATION This applicationis a continuation-in-part of application Ser. No. 172,920 filed Aug. 18,I971 and now abandoned.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention isdirected to new organic compounds and is particularly concernedwithnovel 4-[ a-phenyI-otolyl ]-3,5-disubstituted-4I-I- l,2,4-triazoles, processes for the production thereof, and processes forthe production of substituted 2'-[3-substituted-5-aminomethylsubstituted-4H-l,2,4 triazol-4-yl]benzophen0nes. The invention alsoencompasses pharmacologically acceptable acid addition salts of thesecompounds.

The novel compounds and the processes of production therefore can beillustratively represented as follows:

to W

N 1 \N from ll Ill s N R1 R N wherein R is hydrogen, alkyl of l to 3carbon atoms,

inclusive, cycloalkyl of 3 to 8 carbon atoms, inclusive,-

in which R" and R" are defined as hereinabove, usually in an organicsolvent e.g. at 75 C. to the reflux temper- ,ature, to givethe'novel/compounds II from I or the is pyrrolidino, piperidino,morpholino fwherein R R 7 R and R are of hydrogen, alkyl asdefined'above,.- r 1 Lower alkyl groups of l to 3 carbon atoms,inclusive,

I: are exemplified by methyl, ethyl, propyl, and isopropyl.

halogen, or trifluoromethyl. i

The more desirable compounds of formula II have the specific formulallA:

wherein R, is alkyl of l to 3 carbon atoms, inclusive known compounds-IV fromlll f Qorn pound' [I can be oxidizedto'give lvl, v i

v oEs CR -P'rioN OF THE PREFERRED EMBODIMENT l The cycloalkyl group of 3to 8 carbon atoms, inclusive, is exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl;

The novel compounds of the formulae ll including acid addition saltsthereof have sedative, tranquilizing,

and 4-pyridyl; wherein R R R and R are hydrogen, fluoro, chloro, andwherein R' and R" are alkyl defined as above, ortogether is pyrrolidino,piperidino, or morpholino.

The most desirable compounds of formula ll have the specific formulallB:

wherein R," is alkyl of l to 3 carbon atoms, inclusive; and wherein Rand R are hydrogen or chlorine, and wherein R and R" are alkyl definedas above, or together is pyrrolidino, piperidino, or morpholino.

The process of this invention comprises: treating a compound of formulaI or III with formaldehyde and a secondary amine hypnotic, musclerelaxant and anticonvulsant effects in mammals including man and birds.They are also useful as feed additives for increasing growth rate andfeed efficiency of livestock and poultry, milk production duringlactation in the mammalian species and egg production in the avianspecies.

The acid addition salts of compounds of formula I] contemplated in thisinvention, are the hydrochlorides, hydrobromides, hydriodides, sulfates,phosphates, fumarates cyclohexanesulfamates, methanesulfonates and thelike, prepared by reacting a compound of formula II with an excess ofthe selected pharmacologically acceptable acid.

Sedative effects of 4-[4-chloro-a-phenyl-o-tolyl1-5-pyrrolidinomethyl-3-methyl-4H-1,2,4-triazole are shown by the followingtests in mice:

Chimney test: [Med. Exp. 4, (1961)]: The effective intraperitonealdosage for 50% of the mice (ED is 79 mg./kg. The test determines theability of mice to back up and out of a vertical glass cylinder within30 seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes 10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes-indicatestranquilization. ED equals the dose of the test compound at which 50% ofthe mice remain in the dish. The ED (intraperitoneal administration) inthis test is 40 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is 79 mg./kg.

Nicotine antagonism test: Mice in a group of 6 are injected with thetestcompound[4-[4-chloro-a-phenyl-otolyl]-5pyrrolidinomethyl-3-methyl-4l-l-l,2 ,4 triazole). Thirty minutes later the mice, including control(untreated) mice, are injected with nicotine salicylate (2 mg./kg.). Thecontrol mice show overstimulation, i.e., 1) running convulsions followedby (2) tonic extensor fits followed by (3) death. An intraperitonealdosage of 36 mg./kg. of the test compound protected 50% of the miceagainst (2) and (3) (ED The above novel triazoles of formula II are alsoim portant as intermediates to produce the known triazolobenzophenonecompounds of formula N which are even more active tranquilizingcompounds. For example, 5-chloro-2-[3-methyl-5-(pyrrolidinomethyl)-l,2,4-triazol-4-yllbenzophenone has ED as follows Dish test 1.3 mg./kg.Pedestal 2.3 mg./kg. Nicotine antagonism test (2) and (3) 0.4 mgJkg. Forthe following benzophenones IV, these values were found:

D dish test P pedestal test Ni nicotine antagonism (3) test Thepharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral and rectal use,e.g., tablets, powder packets, cachets, dragees, capsules, solutions,suspensions, sterile injectable form, suppositories, bougies, and thelike. Suitable diluents or carriers such as carbohydrates (lactose),proteins, lipids, calcium phosphate, cornstarch, stearic acid,methylcellulose and the like may be used as carriers or for coatingpurposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseedoil, peanut oil may be used for preparing solutions or suspensions ofthe active drug. Sweetening, coloring and flavoring agents may be added.

For mammals and birds, food premixes, and starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

As tranquilizers, the compounds of formula II can be used in dosages ofl-50 mg./kg. preferably 5 to mg./kg. in oral or injectable preparationsas described above, to alleviate tension. For compounds of formula [Vthe dosage can be much smaller, for example 0.1 to 2.0 mg./kg. As feedadditives the compounds of formula II can be used in dosages of 0.003mg. to 50 mg./animal/day in a feed to increase growth, feed consumptionand feed efficiency in livestock and poultry, milk production in themammalian species and egg production in the avian species.

The starting compounds I and III in this invention are obtained as shownin the Preparation.

In carrying out the Process of this invention the starting compound ofstructures l or III, in an organic solvent such as diglyme, are heatedtogether with formaldehyde, paraformaldehyde and water, or formalin, anda secondary amine or a secondary amine hydrochloride with additionalhydrochloric acid. The heating is carried out preferably between 75 C.and the reflux temperature of the mixture, about 162 C. for diglyme.Instead of diglyme, other solvents such as ethanol, n-propanol,n-butanol, tetrahydrofuran, mono-or triglyme can be used with monoglymeand diglyme preferred. The secondary amine is used in excess, preferablyfrom 1.2 to 4 times the stoichiometric requirement. In the preferredembodiment of this invention the formaldehyde, paraformaldehyde orformalin is used in excess of 2 to 10 times the stoichiometricallyrequired amount and the hydrochloric acid in an excess of 1.2 to 4 timesthe required amount. The reaction period is between 6 and 48 hours.After the reaction is terminated, the mixture is quenched in a basicsolution of sodium or potassium hydroxide or carbonate and the product(ll or IV) recovered and purified by conventional procedures such asextraction, trituration, chromatography, crystallization, combinationsthereof and the like.

The products of formula ll can be oxidized to give the correspondingbenzophenones IV e.g. with chromic anhydride, in sulfuric acid (Jonesreagent), as shown in Preparations.

The Mannich reaction at C (or C of a 1,2,4-triazole compound is new.

Although Bachman and Hersey [J. Amer. Chem. Soc., 68, 2497 (1946)]demonstrated that benzotriazoles (1,2,3) reacted at nitrogen in aMannich synthesis to give unstable Mannich base products (such as A).

H NR 40 2 2 can be generated from formaldehyde and an amine. Theintermediate iminium salt is a sufficiently reactive electrophilic agentto attack such relatively reactive aromatic nuclei as phenol andindole". (See House, Modern Synthetic Reactions 2nd Edition, Benjamin,Menlo Park, 1972). Presumably, other reactive aromatic nuclei may beattacked as well. The triazole ring, however, is sufficiently basic tobe protonated under the acidic conditions of the Mannich reaction [(see,for example the X-ray results reported by Hester, Duchamp, andChidester, Tet. Lett. 1609, (1972)] and such protonation will decreaseits reactivity toward electrophilic reagents. Therefore, a successfulMannich reaction on a triazole ring substrate requires a delicatebalance of acid and basic reagents, such as are pres-- ently reported.Only the products of nuclear attack, such as 11 and IV, were formed andwere not contaminated with any side products such as The followingpreparations and examples are illustrative of the processes and productsof the present invention. but are not to be construed as limiting.

The 2-aminobenzophenones used in these preparations are known in the artand are well described including their synthesis in:

J. Org. Chem. 26 4491 (1961);

ibid. 27 3781 (1962); ibid. 30 521 (1965); ibid. 32 3798 (1967);

Helv. Chim. Acta. 45, 3,121,075. Preparation 12-amino-5-chlorobenzophenone hydrazone A mixture of 27.2 g. (0.117 mol.)of 2-amino-5- chlorobenzophenone, in 170 ml. of diethylene glycol, and23 ml. (0.45 mol.) of 99% hydrazine hydrate is refluxed for 7 hours. Thesolution is allowd to cool overnight to room temperature. The lightgreen-colored solid which resulted is mixed with 400 ml. of water andextracted into benzene; the layers are separated and the benzene portiondried over anhydrous magnesium sulfate and concentrated. Crystallizationof the residue from ether/hexane affords 13.5 g. (46.8%) of white fluffyneedles of 2-amino-5-chlorobenzophenone hydrazone of melting point133133.5 C.

2226 (1962); US. Pat.

Anal. calcd. for C H ClN z C. 63.55; H, 4.93; N. 17.11;Cl, 14.43. Found:C. 63.58; H, 4.95; N, 17.32; Cl. 14.39.

A second crop (6.0 g., 21%) of needles has a melting point of 132134 C.Preparation 2 2-amino-2,5-dichlorobenzophenone hydrazone In the mannergiven in Preparation 1, 2-amino-2,5- dichlorobenzophenone is refluxedwith hydrazine hydrate in diethylene glycol to give 2-amino-2,5-dichlorobenzophenone hydrazone, as an oil. Preparation 32-amino-5-chloro-2 ,6 'difluorobenzophenone hydrazone 1n the mannergiven in Preparation 1, 2-amino-5- chloro-2,6'-difluorobenzophenone isrefluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2,6'-difluorobenzophenone hydrazone.

Preparation 4 2-amin0-2-chloro 5-nitrobenzophenone hydrazone l 1n themanner given in Preparation 1, 2-amino-2- chloro-S-nitrobenzophenone isrefluxed with hydrazine hydrate indiethylene glycol to give2-amino-2-chloro- 5-nitrobenzophenone hydrazone. Preparation 52-aminobenzophenone hydrazone In the manner given in Preparation 1,2-aminobenzophenone is refluxed with hydrazine hydrate in diethyleneglycol to give 2-aminobenzophenone hydrazone. Preparation 62-benzyl-4-chloroaniline Potassium hydroxide pellets (16.1 g. 245 mmol)are ground and dissolved in ml. of refluxing diethylene glycol. Volatilematerials are distilled until the temperature of the liquid reaches 200C. The solution is then cooled to room temperature and 13.5 g. (54.6mmol) of 2-amino-5-chlorobenzophenone hydrazone is added while thesyrupy liquid is gently reheated. At C. all

the hydrazine has dissolved. The temperature is main A nalncalcd. for CH ClN:

44; Cl. 16.28. Found: C. 71.55; 5

6. 6. 8; Clv 16.16.

H, 5.56; N. H. 5.51; N,

Preparation 7 2-(o-chlorobenzyl)-4-chloroaniline 1n the manner given'inPreparation 6, 2amino-2',5- dichlorobenzophenone hydrazone is refluxedwith potassium hydroxide in diethylene glycol to give 2-(0-chlorobenzyl)-4-chloroaniline of melting point 64-65 C. Preparation 84-chloro-a-(2,6-difluo'rophenyl)-o-toluidine In the manner given inPreparation 6, 2-amino-5- chloro-2',6'-difluorobenzophenone hydrazone isrefluxed with potassium hydroxide in diethylene glycol to give4-chloro-a-(2,6-difluoropheny1)-o-toluidene. Preparation 92-(o-Chlorobenzyl)-4-nitroaniline In the manner given 'in Preparation 6,2-amino-2- chloro-S-nitrobenzophenone hydrazone is refluxed withpotassium hydroxide in'diethylene glycol to give 2-(o-chlorobenzyl)-4nitroaniline.

Preparation 10 2-benzylaniline In the manner given in Preparation 6,2-aminobenzophenone hydrazone is refluxed with potassium hydroxide indiethylene glycol'to give 2-benzylaniline of melting point 5152 C.Preparation 11 1-acetyl 2-[N-(Mchloro-a-phenyl-o:tolyl)-formimidoyl]hydrazine A mixture of"3 .37 g. (15.5 mmol) of2-benzyl-4- chloroaniline, 5.52 g. (37.3 mmol) of trietliylorthoformateand a'catalytic amount of the starting amine hydrochloride is refluxed 5hours to distill off ethanol. The orange solution is permitted to coolto room temperature. This crude oil is then dissolved in 25 ml. ofabsolute ethanol and 2f35 g. (32.0 mmol)of acethydrazide is added. Afterstirring the solution for 0.5 hours, a white solid precipitates.Stirring is continued for an additional 2.5 hours and the solid isdissolved in ethyl I Anal. calcd. for c u cm oz .35; N, l3.93; Cl.11.74. H. 5.22, N. 13.94; Cl. 11.57.

C, 6 Found: C, 6

A second crop (0.8 g. 17%) has a melting point l57160 C. Preparation 121-isonicotinoyl-2-[N-(4-chloro-a-phenyl-o-tolyl )formimidoyl IhydrazineA mixture of 10.12 g. (46.5 mmol) of 2-benzyl-4- chloroaniline and 16.57g. (101.9 mmol) of triethylorthoformate is refluxed in a 50 ml. roundbottom flask to distill off ethanol. After an additional 2-4 hourheating period, the liquid in the flask is permitted to cool to roomtemperature and the resulting reaction mixture dissolved in 100 ml. ofabsolute ethanol. To this solution is added 13.2 g. (96 mmol) ofisoniazid. The mixture (isoniazid is not very soluble in cold ethanol)is stirred at room temperature overnight. The solid is. filtered anddissolved in 700 ml. of tetrahydrofuran and concentrated to a volume of350 ml. Hexane is cautiously added until the solution just becomescloudy. A white solid (5.3 g. 31%) is collected, melting point l73l78 C.Recrystallization of a small sample from tetrahydrofuran increases themelting point to 180182 C. A sample crystallized fromdimethylformamide-water has a melting point of 193194 C.

The mother liquors from the first crystallization yield 3.67 g. (22%) ofwhite powder of melting point l78l82 C. The analytical sample ofl-isonicotinoyl- 2-[N-(4-chloro-a-phenyl-o-tolyl(formimidoyl]hydra-,zine has a melting point of 180-182 C.

Preparation 13 l-acetyl-2-[N-[4-chloro-a-(o-chlorophenyl )-o-tolylformimidoyl hydrazine In the manner given in Preparation 11,2-(o-chlorobenzyl)-4-chloroaniline and triethylorthoformate is refluxed,then after 4 hours heating, treated, at room temperature, withacetylhydrazide to give l-acetyl-Z- [N-[4-chloro-a(o-chlorophenyl)-o-tolyl]formimidoyl]hydrazine; yield 93%; melting pointl96.5-l99.5 C.

Anal. calcd. for C H Cl N Oz C, 57.15; H, 4.50; N. 12.50; Cl. 21.09.Found: C. 57.06;1-1, 4.41; N, 12.26; CI, 21.2].

perature with cyclopropylcarbonyl hydrazide to give1-cyclopropylcarbonyl-2-[N-[a-(o-chlorophenyl)-4-nitro-o-tolyl]formimidoyl]-hydrazine. Preparation 16l-benzoyl-2-[N-(a-phenyl-o-tolyl)formimidoyl lhydrazine In the mannergiven in Preparation 11, 2-benzylaniline and triethyl orthoformate isrefluxed, then after 5 hours, treated, at room temperature, withbenzoylhydrazide to givel-benzoyl-2-[N-(a-phenyl-o-tolyUformimidoyl]hydrazine. 1 Preparation 174-[4-chloro-a-(phenyl)-o-tolyl]-3- methyl-4H-1,2,4-triazole To a oneliter flask is added 28.4 g. (94.2 mmol) of l-acetyl-2-[N-[ 4-chloro-a-(phenyl )-o-tolyl Iformimidoyl l-hydrazone and 400 ml. of diglyme. Themixture is heated to reflux and at all the solid starting materialdissolves. Pyridine (20 ml.) is added and the solution is refluxedovernight (20 hours). About 200 ml. of pyridine, water and diglyme areremoved by distillation under reduced pressure and to the remaining coldreaction solution is added 1,500 ml. of (reagent grade) hexane.Trituration in an ice bath yields 20.8 g. (78%) of4-[4-chloro-a-(phenyl)-o-tolyl]-3-methyl- 4H-1,2,4-triazole of meltingpoint -l39 C. An analytical sample is obtained on recrystallization fromethyl acetate/hexane having a melting point of 142 C.

Anal. calcd. for'C H ClN z H. 4. H. 4 14.99: Cl. 12.61.

Preparation 18 4-[4-chloro-a-(phenyl)-o-tolyl]-3-(4- pyridyl )-4H-l,2,4-triazolel-lsonicotinoyl-2-[N-(4-chloro-a-phenyl-o-tolyl)formimidoyl]hydrazine(3.64 g., 10.0 mmol) is placed in a 200 ml. round bottom flask with 60ml. of diglyme. The mixture is refluxed. At a pot temperature ofapproximately 150 C., all the starting material is dissolved. Refluxingis continued an additional 3 hours and the solution is permitted to coolovernight. The slightly cloudy liquid is dried with anhydrous magnesiumsulfate sodium sulfate and filtered. Hexane is added (900 ml.) and thesolution is placed in a refrigerator after scratching to inducecrystallization. The light brown solid is filtered to yield 2.33 g.(67%) of 4-[4-chloro-a-(phenyl)-o-tolyl]-3-(4-pyridyl)-4H-l,2,4-triazole with a melting pointof 138,-l42 C. An analytical sample is prepared mostconveniently byrecrystallization first from aqueous methanol to give plates having amelting point 146C. followed by recrystallization from ethylacetate/hexane to yield white prisms of melting point 145-146.5 C.

Anal. calcd. for C H Chz C Found: C.

Anal. calcd. for cmH aclgNgl C. 60.39; H. 4.12; N, 1321; C1, 22.28.Found: C. 60.13; H. 4.02; N, 13.34; Cl. 22.52.

Preparation 204-[4-chloro-a-(2,6-difluorophenyl)-otlyl]-3-ethyl-4H-1,2,4-triazole Inthe manner given in preparation 17, l-propionyl-2-[N-[4-chloroa-(2,6-difluorophenyl)-o-tolyl]formimidoyl]-hydrazineishfeated with diglyme and pyridine to give4-[4-chloro-a-(2,6-difluorophenyl)-otolyl]-3-ethyl-4H-l ,2,4-tria zole.Preparation 21 4-[a-(o-chlorophenyl)-4-chloro-otolyl]-3-cyclopropyl-4H-l ,2,4-triazole In the manner given in Preparation17,l-cyclopropylcarbonyl-2-[N-[a-(o-chlorophenyl)-4-chloro-otolyl]-formimidoyl]-hydrazineis heated with diglyme and pyridine to give4-[a-(o-chlorophenyl)-4-chloro-otolyl]-3-cyclopropyl-4H-l ,2,4-triazole.Preparation 22 4-[a-(phenyl)-o-tolyl-3phenyl-4I-I- 1,2,4-triazole In themanner given in Preparation 17, l-benzoyl-2-[N-(a-phenyl-o-tolyl)formimidoyllhydrazine is heated with diglyme andpyridine to give 4-[a-(phenyl)-otolyl1-3-phenyl-4H-1,2,4-triazole;Preparation 23 -chloro-2-(3-methyl-4I-1-1 ,2,4-trizol-4-yl)-benzophenone Jones Reagent (0.5 ml.), was added to a solution of4-[4-chloro-a-(phenyl)-o-toly1]-3-methyl-4H- l ,2,4- triazole (0.285 g.,1 .00 mmol.) in 1 ml. of glacial acetic acid. The solution was stirredfor 2 hours at room temperature and 4 hours at reflux (steam bath). Anadditional 0.5 ml. of Jones Reagent was added and the solution wasrefluxed for l more hour. The reaction mixture was poured into 50 ml. of5% aqueous sodium hydroxide and extracted with chloroform. Thechloroform extract was dried overv anhydrous magnesium sulfate andconcentrated on a rotary evaporator (Rota Vap) to leave a yellow solid.Crystallization from ethylv acetate/hexane afforded 180 mg. (61%) of5-chloro-2- (3-methyl-4H-l ,2,4-triazol-4-yl)benzophenone as whiteprisms of melting point 164166 C. Recrystallization changed the meltingpoint to 167.5l69 C. identical to that of an authentic sample.

Preparation 24 2,5-dichloro-2-(3-methyl-4H-1,2,4-

' triazol-4-yl )benzophenone In a ml. flask, 315 mg. (0.99 mmol.) of4-[4- chloro-a-(o-chlorophenyl)-o-tolyl]-3-methyl-4H- 1,2,4-triazole wasdissolved in 1.0 ml. of acetic acid and 1.0 ml. of Jones reagent. Themixture was refluxed for two hours and worked up by quenching in 40 ml.of 7% aqueous sodium hydroxide and extracting with chloroform. Theorganic layer was dried and crystallized from ethyl acetatezhexane 1:2)to give 170 mg. of 2',5- dichloro-2-( 3-methyl-4I-I-l ,2,4-triazol-4-yl)benzophenone as prisms of melting point 147.5148.5 C.

Anal. calcd. for C H CIN O:

C. 57.85; H, 3.34; N. 12.65; Cl. 21.35. Found: C. 57.70; H. 3.21; N.12.47; C1. 21.58.

Preparation 25 5-chloro-2',6-difluoro-2-(3-ethyl-4H-1,2,4-trizol-4-yl)benzophenone In the manner given in Preparation 23,4-[4-chloroa-(2,6-difluorophenyl )-o-tolyl]-3-ethyl-4I-Il ,2,4-

green in color." A small portion is. removed and quen'ched'in 5% sodiumhydroxide and extracted with chloroform, dried over anhydrous magnesiumsulfate,

and concentrated and analyzed by thin layer chromatography. Anadditional 1.5m1. of Jones reagent is added and the refluxing continuedfor another 3.5 hours. Thereaction is permitted to cool to roomtemperature overnight and worked up as described above to give 400 mg.of slightly brown solid. Recrystallization from chloroform-hexaneaffords 380 mg. of 5- ch1oro-2-[ 3-(4-pyridyl)-4H-l ,2,4-triazol-4-ylIbenzophenone as fine white needles of melting point 250 25l C. Theanalytical sample (recrystallized from chloroform/methanol) has amelting point Anal. calcd. for C H ClNp:

c, 66.58; H, 3.63; N. 15.53; Cl. 9.83. Found: c, 66.45; H. 3.65; N,15.36; Cl. 9.88.

Preparation 27 2',5-dichloro-2-(3-cyclopropyl-4Hl,2,4rtriazol-4-yl)benzophenone In the manner given on preparation 234-[a-4 chloro a-(o-chlorophenyl )-o-to1yl]3-cyclopropyl-4H-1,2,4-triazole was oxidized with Jones reagent to give2',5-dichloro-2-(3-cyclopropyl-4H-1,2,4-triazol-4- yl)benzophenone. e

In the manner given in the preceding preparations other2-(3-substituted4H-1 ,2,4-triazol-4-yl)benzophenones compounds can' beproduced from the corresponding 2-amino-benzophenones. Representativecompounds, thus obtained include: 3',5-dibromo-2-(3- propyl-4I-I-l,2,4-triaz ol-4-yl)benzophenone;

2 '-bromo-6-fluoro-2-( 3-cyclobutyl-4H-1 ,2 ,4-triazol-4- yl)-benzophenone; 2-fluoro-4-ethyl-2-( 3-cyclopentyl-4H- l ,2,4-triazol-4-yl)-benzophenone; 4'-diisopropyl-2-(3-cyclohexyl-4H-1,2,4-triazol-4-y1)-benzophenone; 3-ethyl-2-[ 3-( 3-pyridyl )-4H- 1,2,4-triazol-4-yl]-benzophenone;4-bromo-5-chloro-2-(3-cyclooctyl-4H-1,2,4-triazol-4- yl)-benzophenone;4- fluoro-2'-[ 3-( 2'pyridyl )-4I-I-1 ,2,4-triazol-4-yl1-benzophenone;2',4'-difluoro-4-isopropyl-2-[3-(3pyridy1)-4H-1,2,4-trlazol-4-yl]-benz0phenone;4,6-difluoro-2-(3-isopropyl-4H-1,2,4-triazol-4-yl)benzophenone;2',6',4,5-tetraethyl-2-[3-cyclopropyl-4H- l ,2,4-triazol-4-yl)benzophenone; 2 ,5 -dichloro-2-[ 3-(4-pyridyl )-4H- 1,2,4-triazol-4- yl benzophenone;

5 -propyl-3 '-trifluoromethyl-2-( 3-ethyl-4H- l ,2,4- triazol-4-yl)benzophenone;

5-methyl-2-trifluoromethyl-2-(3-methyl-4H-1,2,4-triazol-4-y1)benzophenone; 3-propyl-2 ',4-diethyl-2-( 3-propy1-4H- 1 ,2,4-triazol-4- yl )-benzophenone;5-fluoro-2-chloro-(3-methy1-4H-1,2,4-triazol-4- yl)benzophenone and thelike.

The benzophenones IV described in Examples 25 to 27 can be converted tothe corresponding triazolobenzodiazepines:

EXAMPLE 1 4-[4-chloro-a-phenyl-o-toly1l-5-pyrrolidinomethyl-3-methyl-4H- 1 ,2,4-triazole A mixture of 0.60 ml. of 37% formalin(0.22,g., 7.4 mmol), 0.250 ml. of pyrrolidine (boiling point 85") (0.213g., 3.0 mmol) and 1.00 ml. of 2.0N hydrochloric acid is dissolved in 2.0ml. of diglyme in a 20 ml. flask fitted with a reflux condenser andmagnetic stirrer bar. Solid 5-chloro-[4-ch1oro-a-phenyl-o-tolyl]-3-methyl-4H-l,2,4-triazole (0.2835 g., 1.00 mmol) is added, and themixture is refluxed for 16 hours on a steam bath. The reaction mixtureis quenched by cooling and pouring it into an aqueous 5% sodiumhydroxide solution and extracting with benzene. The benzene layer isdried over anhydrous magnesium sulfate, concentrated and diluted withhot ethyl acetate and hexane. On cooling 0.208 g. (56.7%) of colorlessprisms are obtained, melting point l38-142 (decomp). Recrystallizationfrom ethyl acetate/hexane affords 0.156 g. of4-[4-chloro-a-phenyl-o-tolyl]-5-pyrrolidino-methpiperidinomethyl-3-ethyl-4H-1,2,4-triazoleIn the manner given in Example 1,4-[4-chloro-a-(och1oropheny1)-otolyl]-3-ethyl-4H-1,2,4-triazole,dissolved in diglyme, is heated to reflux with formalin, piperidine and2N hydrochloric acid at 100 C. to give4-[4-chloro-a-(o-chlorophenyl)-o-to1yl]-5-piperidinomethyl-3-ethyl-4l-I- l ,2,4-triazo1e.

EXAMPLE 3 4-[ 4-chl0r0-a-( o-chlorophenyl )-o-tolyl-5-pyrrolidinomethyl-3-methyl-41-I-1,2,4-triazole In the manner given inExample 1, 4-[4-chloro-a-(ochlorophenyl)--tolyl]-3-methyl-4H-1 ,2,4-triazole. dissolved in diglyme is heated to reflux with formalin,pyrrolidine and 2N hydrochloric acid at 100 C. to give 4-[4-chloro-a-(ch1orophenyl)-o-tolyl]-5-pyrrolidinomethyL3-methyl-4I-I-1,2,4-triazoleof melting point 140149 C. 1

Anal. calcd. for C, H,,C1,N

C. 62.85; H. 5.53; 13.96; C1. 17.67. Found: C 62.64; 1-I, 5.56;

N, N. 14.05; Cl. 17.65.

EXAMPLE 44-[4-chloro-a-(o-chlorophenyl)-o-tolyl]-5-dimethylaminomethyl-3-( methyl)-4H- 1 ,2,4-triazole In the manner given in Example 1,4-[4-chloro-a-(ochlorophenyl )-o-toly1]-3-( methyl )-4H- 1,2,4-triazole, dissolved in diglyme, is heated to reflux with formalin,dimethylamine and 2N hydrochloric acid at C. to give4-[4-chloro-a-(o-chlorophenyl)]-o-toly1]-5-dimethylaminomethyl-3-(methyl)-4H-1,2,4-triazole.

EXAMPLE 54-[4-chloro-a-(o-chlorophenyl)-o-tolyl]-5-morpholinomethyl-3-ethyl-4H-1,2,4-triazole1n the manner given in Example 1, 4-[4-chloro-a-(chlorophenyl)-o-tolyl]-3-cyclopropyl-4H-1.2,4- triazole, dissolved indiglyme, is heated to reflux with formalin, morpholine and 2Nhydrochloric acid at 100 C. to give4-[4-ch1oro-a-(o-chlorophenyl)-o-tolyl]-5-morpholinomethyl-3-cyclopropyl-4H-1,2,4-triazole.

EXAMPLE 64-[4-fluoro-a-(o-chlorophenyl)-o-to1yl]-5-diethy1aminomethyl-4H-l,2,4-triazole 1n the manner given in Example 1,4-[4-fluoro-a-(ochlorophenyl)-o-toly1]-4H-1,2,4-triazo1e dissolved indiglyme, is heated to reflux with formalin, diethylamine and 2Nhydrochloric acid at 100 C. to give 4-[4-fluoro-a-(o-chlorophenyl)-o-tolyl]-5-diethylaminemethyl-4H-;1,2,4-triazole.

EXAMPLE 7 4-[a-phenyl-o-tolyl]-5-dipropylaminomethyl-3-phenyl-4H-l,2,4-triazole In the manner given in Example 1,4-[oz-phenyl-otolyll-3-phenyl-4H- 1 ,2,4-triazole, dissolved in diglyme,is heated to reflux with formalin, dipropylamine and 2N hydrochloricacid at 100 C. to give4-[a-phenyl-otolyl]-5-dipropylaminomethy1-3-phenyl-4H-1,2,4- triazole.

EXAMPLE 8 4-[ 5-bromo-a-( p-trifluoromethylphenyl )-o-tolyl l-S-dipropylaminomethyl-3-ch1oro-4H-1,2,4-triazole 1n the manner given inExample 1, 4-[5-bromo-a-(ptrifluoromethylphenyl )-o-tolyl]-3-chloro-4H-1 ,2,4- triazole, dissolved in diglyme, is heated toreflux with formalin, dipropylamine and 2N hydrochloric acid at 100 C.to give4-[5-bromo-a-(p-trifluoromethylphenyl)-o-tolyl]-5-dipropylaminomethyl-3rchloro-4H-1,2,4-triazole.

EXAMPLE 9 4-[5-fluoro-a-(o-chlorophenyl)-otoly1]-5- piperidinomethyl-4H-1 ,2,4-triazole In the manner given in Example 1,4-[5-fluoro-(ochloro)-o-tolyl]-4l-I-l,2,4-triazole. dissolved indiglyme, is heated to reflux with formalin, piperidine, and 2Nhydrochloric acid at 100 C. to give 4-[5-fluoro-a-(o-chlorophenyl)-o-to1yl]-5-piperidinomethyl-4I-1-1 ,2,4-triazo1e.

EXAMPLE l0 5-chloro-2-[3-methy1-5-( pyrrolidinomethyl)-4H- 1,2,4-triazo1-4-yl]benzophenone A solution of 3.0m]. of 37% formalin(1.11 g. or 37.0

mmol), 1.25 ml. of distilled (85) pyrrolidine (1.07 g., 15.0 mmol) and7.50 ml. of 2N hydrochloric acid, in 10 ml. of diglyme is added to a 50ml. flask, fitted with a reflux condenser and magnetic stirrer bar.1.488 g. of -chloro-2-( 3-methyl-4H-1 ,2,4-triazol-4-yl )benzophenone isadded and the atmosphere above the reaction vessel is evacuated andreplaced with nitrogen several times. The solution is refluxed undernitrogen for 17 hours. lt is quenched by pouring into approximately 40ml. of 5% aqueous sodium hydroxide and extracting with four 30 ml.portions of benzene. The benzene extracts are combined, dried overanhydrous magnesium sulfate and concentrated in a rotating evaporationvessel (rotavap). The resulting diglyme solution is heated on a steambath, diluted with hexane and set aside to cool. In this way 1.04 g. ofa white solid is collected. This powder is recrystallized from ethylacetate/hexane to give 0.82 g. of white needles of5-chloro-2-[3-methyl-S-(pyrrolidinomethyl)-4H-1,2,4-triazol-4-yl]benzophenoneof melting point 169.5171.5 C.

Anal. calcd. for C, H,,ClN O:

56; N. 14.71: Cl. 9.31. Found: C. 66.00; H, .84;

N. 14.44; Cl. 8.94.

EXAMPLE 1] acetic acid. The mixture is refluxed for 3 hours, cooled andquenched on 5% aqueous sodium hydroxide solu-' tion and extracted withchloroform. The chloroform layer is dried (magnesium sulfate) andconcentrated. The residue is crystallized from ethyl acetate/hexane togive 5-chloro-2-[3-methyl-5-(pyrrolidinomethyl)-4H-1,2,4-triazol-4-yll-benzophenone of melting point 169-170 C.

EXAMPLE 12 5-chloro-2-[ 3-methyl-5-(morpholinomethyl )-4H-1,2,4-triazol-4-yl]benzophenone A mixture of 3.0 ml. of 37% formalin(1.1 g., 37-

mmol), 1.31 ml. of morpholine (1.31 g., 15.0 mmol) and 7.5 ml. of 2Nhydrochloric acid, dissolved in ml. of diglyme, is placed in a 50 ml.flask with magnetic stirrer bar and reflux condenser. The solid 5chloro-2- [3-methyl-1, 2,4-triazolo-4-yl]benzophenone 1.488 g., 5.00mmol) is added in one portion, and the solution is refluxed for 24hours. ltis worked up by quenching in 5% aqueous sodium hydroxideextracting with benzene, drying the benzene extracts over magnesium sulfate and concentrating on a rotary evaporator. The resulting oil issubjected to column chromatography (silica Gel G, 10%methanol-chloroform as eluent). One hundred and fifty ml. fractions arecollected. Fractions and 21 containthe pure product. Fraction 22contains primarily the product contaminated with an unknown material oflower Rf. Trituration of fractions 20 and 21 in ether separates theproduct'from a gummy residue to give, after removal (under vacuum) inether: 500 mg. of solid 5-chloro -2-'[3-methyl-5-(morpholinomethyl)-4H-1 ,2,4-triazol-4-yl]benzophenone of melting point 128-130 C.Recrystallization yields 350 mg. of large prisms of melting pointl28.5-l30.5 C.

c. 63.56; H. 5.34; N. 14.12; Cl. 8.93. Found: c. 63.41; 11. 5.37; N.14.21; c1, 9.0a.

EXAMPLE l3 EXAMPLE l4 5-chloro-2-(3-methyl-5-diethylaminomethyl-4H-1,2,4-triazol-4-yl )benzophenone 1n the manner given in Example 10,5-chloro-2-[3- methyl-4H-1,2,4-triazol-4yllbenzophenone, diethylamine,formalin, diglyme, and hydrochloric acid are heated to reflux withstirring to give 5-chloro-2-[3-methyl-5-diethylaminomethyl-4H-1,2,4-triazol-4- yllbenzophenone, meltingpoint 109-1 10 C.

65. Found: C. 65.

EXAMPLE 15 6-chloro-5-propyl-3 '-trifluoromethyl-2-[ 3-ethyl-5dipropylaminomethyl-4H- l ,2,4-triazol-4-yl ]benzophenone In the mannergiven in Example 10, 6-chloro-5-propyl-3"trifluoromethyl-2-[3-ethyl-4H-1,2.4-triazol-4- yl)benzophenone,dipropylamine, formalin, diglyme,

and hydrochloric acid are heated to reflux with stirring to give6-chloro-5-propyl-3'-trifluoromethyl-2-[3- ethyl-S-dipropyl-amino-methyl-4H-1 ,2,4-triazol-4- yllbenzophenone. a

EXAMPLE 16 lO9-l 15 C.

Anal. calcd. for C H Cl;N.O:

C. 60.73; H, 4.85; N. 13.49; Cl. 17.07. Found: C, 60.64; H, 4.86; N.13.61; Cl, [7.71.

EXAMPLE 17 5-bromo-4'-ethyl-2-( 5-morpholinomethyl-4H- l ,2,4-triazol-4-yl)benzophenone in the manner given in Example 10, -bromo-4'-I ethyl-2-[4H-l,2,4-triazol-4yl]benzophenone, morpholine, formalin,diglyme and hydrochloric acid are heated to reflux under stirring to"give 5-bromo-4'-" ethyl-2-[5-morpholinomethyl-4H-l ,2 ,4-triazol-4-yl]-benzophenone.

EXAM P LE 1 8 5-methyl-2-trifluoromethyl-Z-[,3-methyl-5-piperidinomethyl-4H- l ,2,4-triazol-4-yl ]benzophenone 1n the mannergiven in Example 10,S-methyl-Zf-trifluoromethyl-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone,piperidine, formalin, diglyme, and, hydrochloric acid are heated toreflux under stirring to give 5-methyl-2'-trifluoromethyl-2-[3-methyl-5-piperidinomethyl-4H-1,2,4-triazol-4-y1]benzophenone.

EXAMPLE l9 2',5-dichloro-2-[3-(dimethylamino)methyl-S-methyl-4H-1,2,4-triazol-4-yl]benzophenone inthe manner given in Example 10, 2,5-dich1oro-2 v(3-methyl-4H-l,2,4-triazol-4-yl)benzophenone, 7 dimethylamine,formalin,diglyme, and hydrochloric acid are heated to reflux under stirring togive 2',5-dichloro- 2-[3-(dimethy1amino)methyl-5-methy1-4H-1,2,4-triazol-4-yl -benzophenone.

EXAMPLE 2O 5-chloro-2',6'-difluoro-2-[3-methyl-5-diethylaminomethyl-4H-l,2,4-triazol-4-yl]benzophenone In the manner given in Example 10,5-chloro-2,6'- difluoro-2-[3-ethyl-4H-l ,2,4-triazol-4-yl ]benzophenone,diethylamine, formalin, diglyme and hydrochloric acid are heated toreflux under stirring to give 5- chloro-2 ,6 '-difluoro-2-[3-ethyl-5-diethylaminomethy1-4H- l ,2,4-triazol-4-yl]benzophenone.

EXAMPLE 21 5-fluoro-2 '-chloro-2-[ 3-methyl-5 -piperidinomethyl- 41-1-1,2 ,4-triazol-4-yl]benzophenone;

In the manner given in Example 10, 5-fluoro-2'- chloro-2-[ 3-methyl-4H-1,2,4-triazol-4-yl benzophenone, piperidine, formalin, diglyme, andhydrochloric acid are heated to reflux under stirring to give S-fluoro-2-chloro-2-[3-morpholino-5-piperidinomethyl-4H- 1,2,4-triazol-4-yl]-benzophenone.

EXAMPLE 22 5-chloro-2-[3-methy1-5-(piperidinomethyl )-4H- 1 ,2,4-triazol-4-yl]benzophenone hydrochloride In the manner given in Example10, 5-chloro-2-(3- methyl-41+1,2,4-triazol-4-yl)benzophenone,piperidine, formalin, diglyme and hydrochloric acid are heated to refluxwith stirring under a nitrogen atmosphere to give5-chloro-2-[3-methyl-5-(piperidinomethyl )4H- 1 ,2,4-triazo1-4-yl]-benzophenone hydrochloride, fine needles of melting point 226-245(decomp.)

In the manner given in the before-going Examples other startingcompounds of formulae lor 111 can be converted to compounds ll (from I)and 1V (from 111). Representative compounds, thus obtained, include: 4-[5-trifluoromethyl-a-phenyl-o-tolyl]5-morpholinomethyl-3-ethyl-4H- l,2,4-triazole;

' '4-[4-propyl-6-methyl-a-(p-fluorophenyl)-o-tolyl1-5-piperidinomethyl-3-propyl-3H-1,2,4 triazole;

4-(phenyl-o-tolyl)-5-piperidinomethyl-4H-l ,2 ,4- triazole;

4-[a-(o-chlorophenyl)-o-tolyl]-5 pyrrolidinomethyl- 4H-l ,2,4-triazole;

4-[a-(o-chlorophenyl)-o-tolyl]-5'-piperidinomethyl-3-methyl-4l-l-1,2,4-tria2ole;

4-[ 4,6-dimethyl-a-(o-chlorophenyl )-o-tolyl]-5morpholinomethyl-3-methyl-4H-1,2,4-triazole;

4-[ 5-chloro-a-phenyl-o-tolyl I-S-diethylaminomethyl-3-4H- 1,2,4-triazole;- Y

1 claim: l. A 4-[a-phenyl-o-tolyll-S-aminomethyl-3-substituted-4H-l,2,4-triazole of the formula [1:

wherein R is hydrogen, alkyl of 1 to 3 carbon atoms, inclusive,cycloalkyl of 3 to 8 carbon atoms, inclusive, phenyl, benzyl, orpyridyl, wherein R and R" are alkyl defined as above, or together arepyrrolidino, piperidine, or morpholino; wherein R R R and R arehydrogen, alkyl as defined above, halogen, or trifluoromethyl.

2. A compound according to claim 1 of the formula llA llA wherein R, isalkyl of l to 3 carbon atoms or 4-pyridyl, inclusiye; wherein R R R andR are hydrogen, fluoro. chloro and wherein R and R" are alkyl defined asabove, or together is pyrrolidino, piperidino, or morpholino.

3. A compound according to claim 1 of the formula llB: r v

wherein R, is alkyl of l to 3 carbon atoms, inclusive and wherein R andR are hydrogen or'chlorine, and wherein R and R" are alkyl defined asabove, or

together is pyrrolidino'; piperidii'io, or morpli oliiio.

4. A compound according to claim 3 wherein R is methyl, the group ispyrrolidino, R is hydrogen and R is chloro, and the compound istherefore 4-(4-chloro-l-a-phenyl-otolyl)-5-pyrrolidinomethyl-3-methyl-4H-l ,2,4-triazole.

5. The compound according to claim 3 wherein R,"

I is methyl,

is pyr'rolidino, and R and R are chloro and the compound is therefore4-[4-chloro-a'-(o-chlorophenyl)-otolyl]-5-pyrrolidinomethyl-3-methyl-4H- Lanna-01

1. A 4-(A-PHENYL-0-TOLYL)-5-AMINOMETHYL-3-SUBSTITUTED-4H1,2,4-TRIAZOLEOF THE FORMULA
 11. 2. A compound according to claim 1 of the formula IIA3. A compound according to claim 1 of the formula IIB:
 4. A compoundaccording to claim 3 wherein R1'''' is methyl, the group
 5. The compoundaccording to claim 3 wherein R1'''' is methyl,